What lab tests are recommended for a patient suspected of having fatty liver disease, particularly those with a history of obesity, diabetes, or high cholesterol?

Laboratory Testing for Fatty Liver Disease

Order a comprehensive metabolic panel with liver enzymes (AST, ALT, alkaline phosphatase, bilirubin), complete blood count with platelets, hemoglobin A1c or fasting glucose, fasting lipid panel, INR, albumin, and a standard liver etiology screen as your initial laboratory workup. 1, 2

Primary Laboratory Panel

Your initial blood work should include:

• Liver enzymes: AST, ALT, alkaline phosphatase, total and direct bilirubin to assess hepatocellular injury and cholestasis 1, 2
• Synthetic function markers: Serum albumin, prothrombin time, and INR to evaluate hepatic synthetic capacity 1, 2
• Complete blood count with platelets: Essential to detect thrombocytopenia, which suggests portal hypertension and likely cirrhosis 1, 2
• Metabolic markers: Fasting glucose or hemoglobin A1c to identify diabetes, which is strongly associated with NAFLD 1, 2
• Lipid panel: Fasting triglycerides, total cholesterol, HDL, and LDL to assess dyslipidemia 1, 2

Critical threshold: Use ALT >20 U/L for women and >30 U/L for men as your cutoff for abnormal, not the traditional laboratory reference ranges, as these are more sensitive for detecting NAFLD 2

Excluding Alternative Liver Diseases

You must rule out other causes of chronic liver disease before confirming NAFLD:

• Viral hepatitis: Hepatitis B surface antigen and hepatitis C antibody 1, 2
• Hemochromatosis: Serum ferritin and transferrin saturation 1, 2
• Autoimmune liver disease: ANA, anti-smooth muscle antibody, and anti-mitochondrial antibody 1, 2
• Wilson's disease: Consider ceruloplasmin in patients under 40 years 2

This etiology screen is mandatory when liver enzymes are elevated or when hepatic steatosis is detected on imaging 2

Fibrosis Risk Stratification

Calculate the FIB-4 index as your first-line fibrosis assessment tool using age, AST, ALT, and platelet count 1, 2, 3. This is the preferred initial test recommended by major guidelines.

FIB-4 Interpretation Algorithm:

• Low risk: FIB-4 <1.3 (or <2.0 if age >65 years) effectively excludes advanced fibrosis with high negative predictive value; reassess every 2 years 2, 1, 3
• Indeterminate risk: FIB-4 1.3-2.67 requires second-tier testing with vibration-controlled transient elastography (VCTE), magnetic resonance elastography (MRE), or enhanced liver fibrosis (ELF) panel 2, 3
• High risk: FIB-4 >2.67 (or >3.25) suggests advanced fibrosis; proceed to secondary noninvasive testing or consider liver biopsy 2, 1

Important caveat: In patients with type 2 diabetes or ≥2 metabolic syndrome features, proceed directly to sequential testing with a second noninvasive test regardless of FIB-4 score, as they are at higher baseline risk 2

Pattern Recognition for Disease Severity

Watch for these laboratory patterns that suggest advanced disease:

• AST:ALT ratio >1: Indicates more advanced fibrosis or cirrhosis, as the ratio reverses with disease progression 1, 3
• Thrombocytopenia: Platelet count <150,000/μL suggests portal hypertension 1, 2
• Hypoalbuminemia: Albumin <3.5 g/dL indicates impaired synthetic function 1
• Elevated INR or prolonged PT: Suggests advanced liver disease 1
• Elevated bilirubin: Direct bilirubin elevation indicates cholestasis or advanced disease 1

Imaging as Part of Initial Workup

Order abdominal ultrasonography as your primary screening modality to visualize hepatic steatosis and exclude structural abnormalities like masses or biliary obstruction 1, 2, 3. Ultrasound has 84.8% sensitivity and 93.6% specificity for moderate to severe steatosis 4, though sensitivity drops below 70% when hepatic fat is <30% 2.

For patients with indeterminate ultrasound findings or when precise quantification is needed, MRI with proton density fat fraction (MRI-PDFF) provides excellent steatosis quantification, though it is primarily reserved for clinical trials 3

When to Proceed to Liver Biopsy

Consider liver biopsy when:

• Noninvasive tests are indeterminate or discordant 2, 1, 3
• Clinical suspicion of NASH with advanced fibrosis based on elevated FIB-4 and secondary testing 2
• Need to exclude concurrent chronic liver disease that cannot be ruled out serologically 3, 2
• Patients with cirrhosis indicators (FIB-4 >11.3, VCTE >15 kPa, or MRE >4.6 kPa) to confirm diagnosis and guide surveillance 2

Common Pitfalls to Avoid

Do not exclude NAFLD based on normal ALT alone—up to 50% of NAFLD patients have normal transaminases, and 80% of NASH cases can still be identified with elevated enzymes 2, 3. The absence of elevated liver enzymes does not rule out significant liver disease in high-risk patients with diabetes or metabolic syndrome 2, 5.

Do not assume AST:ALT >1 excludes NAFLD—while this ratio typically suggests alcoholic liver disease, it also occurs in advanced NAFLD with cirrhosis as the disease progresses 3, 4.

Special Considerations for High-Risk Patients

In patients with diabetes mellitus, screen for NAFLD regardless of liver enzyme levels, as cost-effectiveness has been confirmed in this population 2, 3. These patients warrant more aggressive fibrosis assessment given their elevated baseline risk for progressive disease 2.

For patients with metabolic syndrome (≥3 of: abdominal obesity, hypertriglyceridemia, low HDL, hypertension, hyperglycemia), proceed with comprehensive screening as the incidence of NAFLD reaches 40.7% in this population 2